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Glis3: a critical player in the regulation of pancreatic beta cell development

ABSTRACT: Glis3 mutant mice (Glis3zf/zf) die within the first week after birth due to overt diabetes, evidenced by hyperglycemia and hypoinsulinemia. Histopathological analysis showed that Glis3zf/zf mice develop a pancreatic phenotype with a dramatic loss of beta- (insulin) and delta- (somatostatin) cells contrasting a smaller relative loss of alpha- (glucagon), PP- (pancreatic polypeptide), and epsilon- (ghrelin) cells. Glis3zf/zf mice develop ductal cysts with decreased number of primary cilia, while the acini are not significantly affected. Gene expression profiling by microarray analysis demonstrated that the expression of terminal hormonal genes and several transcription factors important in endocrine development were significantly deregulated in Glis3zf/zf mice. During pancreatic development, Glis3 mRNA expression is induced during the secondary transition, a stage of cell lineage specification and extensive patterning. Changes in pancreatic development of Glis3zf/zf mice are noted during and after this stage; the number of cells staining positively for Ngn3, MafA, or Pdx-1 is greatly diminished. These observations indicate that Glis3 plays a key role in the development of mature beta cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE14430 | GEO | 2009/11/15

SECONDARY ACCESSION(S): PRJNA111759

REPOSITORIES: GEO

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T.F. Glis3: a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression

Project description:Glis3 mutant mice (Glis3zf/zf) die within the first week after birth due to overt diabetes, evidenced by hyperglycemia and hypoinsulinemia. Histopathological analysis showed that Glis3zf/zf mice develop a pancreatic phenotype with a dramatic loss of beta- (insulin) and delta- (somatostatin) cells contrasting a smaller relative loss of alpha- (glucagon), PP- (pancreatic polypeptide), and epsilon- (ghrelin) cells. Glis3zf/zf mice develop ductal cysts with decreased number of primary cilia, while the acini are not significantly affected. Gene expression profiling by microarray analysis demonstrated that the expression of terminal hormonal genes and several transcription factors important in endocrine development were significantly deregulated in Glis3zf/zf mice. During pancreatic development, Glis3 mRNA expression is induced during the secondary transition, a stage of cell lineage specification and extensive patterning. Changes in pancreatic development of Glis3zf/zf mice are noted during and after this stage. The population of pancreatic progenitors appears not to be greatly affected in Glis3zf/zf mice; however, the number of neurogenin 3 (Ngn3) positive, endocrine progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly the development of mature pancreatic beta-cells. In addition, we identified evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter indicating that Glis3 is a regulator of insulin gene expression.

2010-01-01 | GSE18172 | GEO

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Glis3 regulates pancreatic beta cells development and maturation

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2016-07-01 | E-GEOD-67238 | biostudies-arrayexpress

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Project description:Loss of transcription factor GLIS3 function in humans and mice leads to the development of neonatal polycystic kidney disease (PKD). To investigate how loss of GLIS3 function in kidney affects postnatal kidney development and PKD, we analyzed the gene expression profiles of kidneys from WT and Glis3-null mice at P7, P14, and P28 by RNA-Seq analysis using Glis3 global KO model Glis3-mCherry and kidney specific knockout model Glis3-PAX8Cre.

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Glis3 regulates pancreatic beta cells development and maturation

Project description:Glis3 is expressed in pancreatic beta and PP cells. To identify down stream target genes of Glis3, we performed microarray analysis using pancreas total RNAs from 1 week-old WT and Glis3KO2 mice. insulin and pancreatic polypeptide (Ppy) was significantly decreased together with several other β cell markers, Glut2 and MafA by microarray analysis. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal Glis3KO2 pancreas still contains a large population of β cells that express Pdx-1, Nkx6.1, and Isl-1; however, insulin production and secretory granules were greatly reduced in these cells. In addition, chromogranin A (ChgA) and Urocortin 3, which are associated with mature β cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic β cell phenotype.

2016-07-01 | GSE67238 | GEO

Induction of insulin gene transcription by Gli-similar KrÃ¼ppel-like zinc finger protein 3, Glis3, in Î±TC1-9 cells

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2016-03-14 | E-GEOD-72566 | biostudies-arrayexpress

Glis3 plays a crucial role in thyroid hormone production

Project description:The serum hormone levels including T3 and T4 were dramatically decreased in Glis3-null mice due to reduced production of thyroid hormones in thyroid. Gene expression profile and EdU incorporation analysis between WT and Glis3-null mice showed that the cell proliferation was greatly reduced in Glis3-null thyroid. Goitergenic diet (low iodine diet; LID) dramatically enhanced serum TSH levels in both WT and Glis3-null mice, however thyroid goiter was observed in WT mice but not in Glis3-null mice. A subset of genes associated with thyroid hormone production including Pendrin (Slc26a4), Nis (Na+/I– symporter, Slc5a5), Duoxa2 (dualoxidase A2), Tpo (thyroperoxidase), and Dio1 (Deiodinase1) was significantly induced in WT but not in Glis3-null mice by LID feeding.

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Examination of Glis3 binding and affects on gene expression in mouse pancreas

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Induction of insulin gene transcription by Gli-similar Krüppel-like zinc finger protein 3, Glis3, in αTC1-9 cells

Project description:In this study, we examined the effect of Glis3 on the transcriptional activation of gene expression, including insulin gene, in pancreatic α-cell line, αTC1-9, which do not express the insulin gene. We demonstrate that Glis3 induces the transcription of the insulin and identified a number of other genes that are induced by Glis3.

2016-03-14 | GSE72566 | GEO

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

Project description:Deficiency in Krüppel-like zinc finger transcription factor, GLI-Similar 3 (GLIS3) in humans is associated with the development of congenital hypothyroidism. However, the functions of GLIS3 in the thyroid gland and by what mechanism GLIS3-dysfunction causes hypothyroidism are unknown. In this study, we demonstrate that GLIS3 acts downstream of thyroid stimulating hormone (TSH)/TSHR and is indispensable for TSH/TSHR-mediated induction of thyroid follicular cell proliferation and thyroid hormone biosynthesis. ChIP-Seq and promoter analysis revealed that GLIS3 is critical for the transcriptional activation of several genes required for thyroid hormone biosynthesis, including the iodide transporters Nis and Pds, indicating that these genes are directly regulated by GLIS3. The repression of cell proliferation regulatory genes is due to the inhibition of TSH-mediated activation of the mTORC1/RPS6 pathway as well as direct transcriptional regulation of several cell division-related genes by GLIS3. Consequently, GLIS3-deficiency prevents the development of goiter as well as the induction of inflammatory and fibrotic genes during chronic elevation of circulating TSH. Our study identifies GLIS3 as a new and key regulator of TSH/TSHR-mediated thyroid hormone biosynthesis and proliferation of thyroid follicular cells, and uncovers a mechanism by which GLIS3-deficiency causes congenital hypothyroidism and prevents goiter development.

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